Don't get blinded by the averages on the last line, they are the reason why (at least some) automatic fitting programs perform so badly.

The interaction energies with the CH3 group got better, but they're totally irrelevant because they're repulsive.

Interaction 1) got substantially worse; I'd try to fix that up.

Interaction 5) got substantially better, at the cost of interaction 6), which got a little bit worse. Unfortunately, out of these two interactions, interaction 6) is more important (lower AI energy). Yet, improving interaction 6) should not lead to a worsening of interaction 3). The carboxylate group is a bit messy and I'm not sure you can improve it, but you can try. I'm not a psychic.

When you're done with that, yes, it's perfectly possible that the final unconstrained values are better than the constrained ones.

Hmm, the charges are not convincingly improved. This seems to be a bit of a tough case; the ranking of interactions 1-6 is significantly different in the QM and the MM. Maybe we should go for a compromise after all, like getting the average difference of 1 and 2 as close to 0 as possible, and same for the average difference of 3,4,5, and 6.

I have finished the part "Target Part".When I do the next "Initial charge optimization using the QM geometry",I'm confused with how to get the file water_constr.inp. Is there any generator to get it? Or should I write it manually? If it's the latter case, how can I prepare "the IC table for surface of interest"? Is there any principles to write this part?

Sorry for so many questions,maybe some are silly. I'm new for CHARMM and I'm really trapped here. Looking forward for your reply.